Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats: Part 1

Abstract

Submicrometer TiO₂ particles, including nanoparticulate fractions, are used in an increasing variety of consumer products, as food additives and also drug delivery applications are envisaged. Beyond exposure of occupational groups, this entails an exposure risk to the public. However, nanoparticle translocation from the organ of intake and potential accumulation in secondary organs are poorly understood and in many investigations excessive doses are applied. The present study investigates the biokinetics and clearance of a low single dose (typically 40–400 μg/kg BW) of ⁴⁸V-radiolabeled, pure TiO₂ anatase nanoparticles ([⁴⁸V]TiO₂NP) with a median aggregate/agglomerate size of 70 nm in aqueous suspension after intravenous (IV) injection into female Wistar rats. Biokinetics and clearance were followed from one-hour to 4-weeks. The use of radiolabeled nanoparticles allowed a quantitative [⁴⁸V]TiO₂NP balancing of all organs, tissues, carcass and excretions of each rat without having to account for chemical background levels possibly caused by dietary or environmental titanium exposure. Highest [⁴⁸V]TiO₂NP accumulations were found in liver (95.5%ID after one day), followed by spleen (2.5%), carcass (1%), skeleton (0.7%) and blood (0.4%). Detectable nanoparticle levels were found in all other organs. The [⁴⁸V]TiO₂NP content in blood decreased rapidly after 24 h while the distribution in other organs and tissues remained rather constant until day-28. The present biokinetics study is part 1 of a series of studies comparing biokinetics after three classical routes of intake (IV injection (part 1), ingestion (part 2), intratracheal instillation (part 3)) under identical laboratory conditions, in order to test the common hypothesis that IV-injection is a suitable predictor for the biokinetics fate of nanoparticles administered by different routes. This hypothesis is disproved by this series of studies.

Keywords:

• Size-selected, radiolabeled titanium dioxide nanoparticles
• intravenous injection
• accumulation in organs and tissues
• translocation across organ membranes
• hepato-biliary nanoparticle clearance

This article is related to:

Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3

Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats: Part 2

Acknowledgements

We would like to thank Sebastian Kaidel, Paula Mayer and Nadine Senger from the Helmholtz Center Munich for their excellent technical assistance, as well as Antonio Bulgheroni, Kamel Abbas, Federica Simonelli, Izabela Cydzik and Giulio Cotogno from the EU-Joint Research Center who strongly supported the nanoparticle radiolabeling activities. We also express our sincere gratitude to Prof. Dr. Barbara Rothen-Rutishauser and David Raemy from the University of Fribourg, Switzerland, who performed the TEM analysis of the TiO₂NP.

This work was partially supported by the German Research Foundation SPP 1313, the EU-FP6 project Particle-Risk (012912 (NEST)), and the EU FP7 projects NeuroNano (NMP4-SL-2008-214547), ENPRA (NMP4-SL-2009-228789) and InLiveTox (NMP-2008-1.3-2 CP-FP 228625-2).

Disclosure statement

The authors declare that they have no financial, consulting, and personal relationships with other people or organizations that could influence (bias) the author’s work.